Search

Introduction: Huntington's disease (HD) is a fatal neurodegenerative disorder caused by an expansion of the CAG trinucleotide repeat in the Huntingtin gene (HTT). Immune activation is abundant in the striatum of HD patients. Detection of active microglia at presymptomatic stages suggests that microgliosis is a key early driver of neuronal dysfunction and degeneration. Recent studies showed that deletion of Tyrobp, a microglial protein, ameliorates neuronal dysfunction in Alzheimer's disease amyloidopathy and tauopathy mouse models while decreasing components of the complement subnetwork., Objective: While TYROBP/DAP12-mediated microglial activation is detrimental for some diseases such as peripheral nerve injury, it is beneficial for other diseases. We sought to determine whether the TYROBP network is implicated in HD and whether Tyrobp deletion impacts HD striatal function and transcriptomics., Methods: To test the hypothesis that Tyrobp deficiency would be beneficial in an HD model, we placed the Q175 HD mouse model on a Tyrobp-null background. We characterized these mice with a combination of behavioral testing, immunohistochemistry, transcriptomic and proteomic profiling. Further, we evaluated the gene signature in isolated Q175 striatal microglia, with and without Tyrobp., Results: Comprehensive analysis of publicly available human HD transcriptomic data revealed that the TYROBP network is overactivated in the HD putamen. The Q175 mice showed morphologic microglial activation, reduced levels of post-synaptic density-95 protein and motor deficits at 6 and 9 months of age, all of which were ameliorated on the Tyrobp-null background. Gene expression analysis revealed that lack of Tyrobp in the Q175 model does not prevent the decrease in the expression of striatal neuronal genes but reduces pro-inflammatory pathways that are specifically active in HD human brain, including genes identified as detrimental in neurodegenerative diseases, e.g. C1q and members of the Ccr5 signaling pathway. Integration of transcriptomic and proteomic data revealed that astrogliosis and complement system pathway were reduced after Tyrobp deletion, which was further validated by immunofluorescence analysis., Conclusions: Our data provide molecular and functional support demonstrating that Tyrobp deletion prevents many of the abnormalities in the HD Q175 mouse model, suggesting that the Tyrobp pathway is a potential therapeutic candidate for Huntington's disease., (© 2024. The Author(s).)

Introduction: This study aimed to determine the baseline knowledge and beliefs, along with the impact of incorporating surgical ergonomics lectures during a residency., Methods: A cohort of 123 Indian surgical residents participated in this educational intervention, which consisted of two educational webinars on ergonomics. Both pre- and post-intervention surveys were electronically sent to the participants. These included questions related to their demographics, prevalence of musculoskeletal (MSK) symptoms, and factors affecting participant awareness of ergonomic recommendations., Results: Seventy-one residents responded to the pre-webinar survey. Eighty-five percent of respondents reported MSK symptoms, with the most common being pain (70%) and stiffness (40%), which the residents attributed to their surgical training. Forty-six residents completed the post-webinar survey. The majority of respondents strongly agreed or agreed that surgical ergonomic educational sessions improved their understanding of the fundamental causes of MSK symptoms and increased their awareness of options available for prevention MSK injuries., Conclusion: The rate of MSK symptoms and/or injury was high among this cohort of surgical residents. These surveys and educational session demonstrated there is limited awareness of the comprehension of ergonomics related to surgical procedures. Our study shows that a simple surgical ergonomic educational intervention can lead to improved understanding of prevention and ergonomic changes., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Migrant and seasonal farmworkers (MSFW) experience disproportionate infection, severe disease and death from COVID-19. This report describes an innovative process to address the safety of MSFW that utilized cohorting that eventually allowed for safe release to work in the fields on a large family farm in Iowa. Methods : Upon worker departure from Mexico, the employer arranged for bus seat assignments, mask use, and hand hygiene practice during the 3-day trip to Iowa. Upon arrival at the farm, surveillance testing and low-density housing cohorting based upon travel seat assignments allowed for early identification of infected workers and appropriate quarantine as per CDC guidelines. Upon completion of isolation or quarantine as appropriate, workers were released to congregate housing and work in the fields. Findings : Compared to a migrant farmworker COVID-19 outbreak without travel pre-planning, the cohorting process produced a 3.5% positivity rate compared to an earlier season July farmworker group on the same farm with a 12.7% positivity rate. Conclusions/Application to Practice : The success of this model points to the power of collaboration between farm employer, health care providers and workers to minimize worker infection and enable safe work in the fields. Increased state and federal support for MSFW protections could support infrastructure to proactively plan for prevention mechanisms to prevent the spread of known communicable disease. With support in place from the top down, employers, workers, and health care providers will be able to prioritize the management of infectious diseases and the needs of essential workers.

Many diseases are linked to dysregulation of the striatum. Striatal function depends on neuronal compartmentation into striosomes and matrix. Striatal projection neurons are GABAergic medium spiny neurons (MSNs), subtyped by selective expression of receptors, neuropeptides, and other gene families. Neurogenesis of the striosome and matrix occurs in separate waves, but the factors regulating compartmentation and neuronal differentiation are largely unidentified. We performed RNA- and ATAC-seq on sorted striosome and matrix cells at postnatal day 3, using the Nr4a1 -EGFP striosome reporter mouse. Focusing on the striosome, we validated the localization and/or role of Irx1 , Foxf2 , Olig2 , and Stat1/2 in the developing striosome and the in vivo enhancer function of a striosome-specific open chromatin region 4.4 Kb downstream of Olig2 . These data provide novel tools to dissect and manipulate the networks regulating MSN compartmentation and differentiation, including in human iPSC-derived striatal neurons for disease modeling and drug discovery., Competing Interests: MC, SS, KT, CC, JM, CG, HB, JB, PA, JF, JC, AR, AN, PC, PR, SM, LE, ME No competing interests declared, (© 2021, Cirnaru et al.)

Migrant and seasonal farmworkers are a vulnerable population with unique health and safety challenges related to the entire spectrum of the social determinants of health. These challenges place migrant and seasonal farmworkers at a disproportionate risk of infection and illness because of the COVID-19 pandemic. This report presents a case study of an early COVID-19 outbreak among migrant farmworkers in Iowa and describes the role that a nimble and responsive mobile federally qualified health center played in the successful mitigation and response to this outbreak. Early during the pandemic, the clinic adopted a new model of service delivery utilizing telemedicine primary care visits, followed by in-person visits when necessary. As the pandemic progressed, clinic staff strategized to provide increased pandemic-related support to agricultural employers and migrant farmworkers across the state. Emphasis was placed on on-site testing and education regarding social distancing, mask utilization, and hand washing. Eventually, as migrant workers were infected and became symptomatic, more complex mitigation strategies such as isolation, quarantine, and clinical follow-up were also implemented. This report describes how a mobile primary care clinic developed a pandemic responsive model to provide successful mitigation of an early COVID-19 outbreak among essential and highly vulnerable migrant farmworkers.

Background: Education on surgical ergonomics during residency training is lacking. This study aimed to determine the feasibility and impact of incorporating surgical ergonomics lectures into residency curriculum., Methods: A survey was distributed to 42 residents with questions regarding demographics, surgical factors, prevalence of musculoskeletal (MSK) symptoms, and awareness of ergonomic recommendations. The residents then received 2 lectures on ergonomics in surgery. A follow up survey was distributed to evaluate the impact of the lectures., Results: Twenty-two residents completed the presession survey. Ninety-one percent reported MSK symptoms attributed to their training. Seventeen residents completed the follow up survey. All reported increased awareness of their own habits while operating and improved understanding of methods to prevent and/or treat work-related injuries. All residents recommended incorporating the lectures as an adjunct to their regular curriculum., Conclusions: The rates of MSK symptoms and/or injury are high among surgeon trainees. Residency is an opportune time to educate on principles of ergonomics and may prevent future injuries., (Copyright © 2020 Association of Program Directors in Surgery. Published by Elsevier Inc. All rights reserved.)

The chromatin landscape of human brain cells encompasses key information to understanding brain function. Here we use ATAC-seq to profile the chromatin structure in four distinct populations of cells (glutamatergic neurons, GABAergic neurons, oligodendrocytes, and microglia/astrocytes) from three different brain regions (anterior cingulate cortex, dorsolateral prefrontal cortex, and primary visual cortex) in human postmortem brain samples. We find that chromatin accessibility varies greatly by cell type and, more moderately, by brain region, with glutamatergic neurons showing the largest regional variability. Transcription factor footprinting implicates cell-specific transcriptional regulators and infers cell-specific regulation of protein-coding genes, long intergenic noncoding RNAs and microRNAs. In vivo transgenic mouse experiments validate the cell type specificity of several of these human-derived regulatory sequences. We find that open chromatin regions in glutamatergic neurons are enriched for neuropsychiatric risk variants, particularly those associated with schizophrenia. Integration of cell-specific chromatin data with a bulk tissue study of schizophrenia brains increases statistical power and confirms that glutamatergic neurons are most affected. These findings illustrate the utility of studying the cell-type-specific epigenome in complex tissues like the human brain, and the potential of such approaches to better understand the genetic basis of human brain function.

Background: Prostaglandins are products of the cyclooxygenase pathway, which is implicated in Parkinson's disease (PD). Limited knowledge is available on mechanisms by which prostaglandins contribute to PD neurodegeneration. To address this gap, we focused on the prostaglandin PGD2/J2 signaling pathway, because PGD2 is the most abundant prostaglandin in the brain, and the one that increases the most under pathological conditions. Moreover, PGJ2 is spontaneously derived from PGD2., Methods: In this study, we determined in rats the impact of unilateral nigral PGJ2-microinfusions on COX-2, lipocalin-type PGD2 synthase (L-PGDS), PGD2/J2 receptor 2 (DP2), and 15 hydroxyprostaglandin dehydrogenase (15-PGDH). Nigral dopaminergic (DA) and microglial distribution and expression levels of these key factors of the prostaglandin D2/J2 pathway were evaluated by immunohistochemistry. PGJ2-induced motor deficits were assessed with the cylinder test. We also determined whether oral treatment with ibuprofen improved the PD-like pathology induced by PGJ2., Results: PGJ2 treatment induced progressive PD-like pathology in the rats. Concomitant with DA neuronal loss in the substantia nigra pars compacta (SNpc), PGJ2-treated rats exhibited microglia and astrocyte activation and motor deficits. In DA neurons, COX-2, L-PGDS, and 15-PGDH levels increased significantly in PGJ2-treated rats compared to controls, while DP2 receptor levels were unchanged. In microglia, DP2 receptors were basically non-detectable, while COX-2 and L-PGDS levels increased upon PGJ2-treatment, and 15-PGDH remained unchanged. 15-PGDH was also detected in oligodendrocytes. Notably, ibuprofen prevented most PGJ2-induced PD-like pathology., Conclusions: The PGJ2-induced rat model develops progressive PD pathology, which is a hard-to-mimic aspect of this disorder. Moreover, prevention of most PGJ2-induced PD-like pathology with ibuprofen suggests a positive feedback mechanism between PGJ2 and COX-2 that could lead to chronic neuroinflammation. Notably, this is the first study that analyzes the nigral dopaminergic and microglial distribution and levels of factors of the PGD2/J2 signaling pathway in rodents. Our findings support the notions that upregulation of COX-2 and L-PGDS may be important in the PGJ2 evoked PD-like pathology, and that neuronal DP2 receptor antagonists and L-PGDS inhibitors may be novel pharmacotherapeutics to relieve neuroinflammation-mediated neurodegeneration in PD, circumventing the adverse side effects of cyclooxygenase inhibitors.

ABTRACT Many sources have highlighted the high incidence of premature cardiovascular events in HIV infected patients. This raises the suspicion of an accelerated aging of the vascular system in this disease characterized by chronic systemic subliminal inflammation and immune dysregulation. Unfortunately all currently available risk assessment algorithms based on traditional risk factors, and even those containing more HIV-specific factors, fail to accurately predict risk in a large proportion of patients. In the general population several models have implemented imaging data to refine risk assessment, and the concept of vascular aging has been of value in improving the performance of these algorithms. It is expected that HIV patients may benefit from a similar approach as it becomes clearer that vascular imaging provides valuable prognostic information in this patient category.

Lead (Pb 2+ ) is a historically well-documented environmental neurotoxin that produces developmental cognitive learning and memory impairments. These early neurodevelopmental impairments cause increased brain excitability via disruption of Ca 2+ mediated signaling during critical periods of synaptogenesis inducing competition with I ca 2+ through NMDA R s resulting in altered brain development and functioning across the lifespan. Interestingly, Pb 2+ has been shown to decrease GABA transport and uptake, decrease spontaneous and depolarization-evoked GABA neurotransmission and lower the expression of glutamic acid decarboxylase (GAD); thereby, limiting excitatory GABAergic influences that regulate early developmental brain excitability and reducing inhibition across mature GABAergic networks. Taurine has been shown to regulate brain excitability in the mature brain through GABA AR mediated inhibition, thereby attenuating improper brain excitability. Mechanistically, taurine is developmentally a potent neuromodulator that acts as a GABA AR agonist and more recently has been reported as a partial agonist for NMDA R s through glycine sites. We investigated the effects of developmental Pb 2+ exposure on the rat's mature inhibitory cognitive control abilities pharmacologically through anxiety and emotional learning-related behaviors and whether taurine could recover Pb 2+ induced neurodevelopmental behavioral deficits later in life. Results showed that Pb 2+ increased anxiety symptoms in the open field and hole board test, increased sensitivity to context fear training with cognitive deficits in both acquisition and extinction learning while producing learning deficits and inabilities in acquiring inhibitory learned associations through the acoustic startle response and pre-pulse inhibition (ASR-PPI) test. Interestingly, taurine recovered Pb 2+ developmentally induced behavioral deficits in the open field and hole board test evidenced by decreased freezing and increased exploration behaviors and facilitated inhibitory dependent ASR-PPI learning to levels higher than controls. In contrast, Baclofen, a GABA BR agonist, dose dependently showed no interaction with Pb 2+ effects on ASR-PPI learning. Thus, taurine may work as an important neuromodulator at both GABA AR s and NMDA R s glycine sites, thereby increasing inhibition, enhancing Ca 2+ -mediated signaling, and decreasing the altered brain excitability, which impedes learning and memory from early Pb 2+ exposure. Taken together our data suggests that GABA AR dependent inhibitory learning is altered by early Pb 2+ exposure and taurine was able to recover these Pb 2+ induced deficits through neuromodulation of GABA AR s and potentially NMDA R s later in life. These findings may pave the way for further exploration of taurine as a pharmacotherapy for neurodevelopmental lead poisoning in both animal and clinical models.

Background: Faecal (f-) calprotectin is a widely used marker for intestinal inflammation. However, extraction procedure is time consuming and cumbersome. The main aim of this study was to evaluate patient-performed extraction of f-calprotectin compared to extraction performed in the laboratory., Methods: A total of 81 adult patients with an established diagnosis of inflammatory bowel disease provided two samples from the same bowel movement, one conventional faeces sample and one sample with a patient administered extraction device. A laboratory technician extracted the conventional faeces sample with the same extraction device., Results: F-calprotectin results from the laboratory-performed extraction and the patient-performed extraction correlated significantly, with a Spearman rank correlation coefficient of 0.92. Method comparison showed a slope of 1.20 (95% confidence interval 1.08-1.36) with intercept of -0.30 (95% confidence interval -9.00 to 4.62). This demonstrates a small proportional difference between the results from the home extracted samples and the results from the laboratory extracted samples, where the home extracted samples are slightly higher. However, six of the 81 patients had made obvious mistakes in the extraction process and their samples were excluded from the study., Conclusions: Patient administered extraction of f-calprotectin can be a realistic alternative for selected patients. However, instructions must be very precise to avoid mistakes.

Prostaglandins (PGs) are produced via cyclooxygenases, which are enzymes that play a major role in neuroinflammation. Epidemiological studies show that chronic treatment with low levels of cyclooxygenase inhibitors (nonsteroidal anti-inflammatory drugs (NSAIDs)) lowers the risk for Alzheimer's disease (AD) and Parkinson's disease (PD) by as much as 50%. Unfortunately, inhibiting cyclooxygenases with NSAIDs blocks the synthesis of downstream neuroprotective and neurotoxic PGs, thus producing adverse side effects. We focus on prostaglandin J2 (PGJ2) because it is highly neurotoxic compared to PGA1, D2, and E2. Unlike other PGs, PGJ2 and its metabolites have a cyclopentenone ring with reactive α,β-unsaturated carbonyl groups that form covalent Michael adducts with key cysteines in proteins and GSH. Cysteine-binding electrophiles such as PGJ2 are considered to play an important role in determining whether neurons will live or die. We discuss in vitro and in vivo studies showing that PGJ2 induces pathological processes relevant to neurodegenerative disorders such as AD and PD. Further, we discuss our work showing that increasing intracellular cAMP with the lipophilic peptide PACAP27 counteracts some of the PGJ2-induced detrimental effects. New therapeutic strategies that neutralize the effects of specific neurotoxic PGs downstream from cyclooxygenases could have a significant impact on the treatment of chronic neurodegenerative disorders with fewer adverse side effects., (© 2016 New York Academy of Sciences.)

Background: The Baumann procedure consists of intramuscular lengthening (recession) of the gastrocnemius muscle in the deep interval between the soleus and gastrocnemius muscles. The goal of the procedure is to increase ankle dorsiflexion when ankle movement is restricted by a contracted gastrocnemius muscle. Unlike the Vulpius procedure, the Baumann procedure truly isolates the lengthening site to the gastrocnemius muscle and does not lengthen the soleus muscle. The Baumann procedure has not previously been studied in cadaver specimens., Methods: The gastrocnemius and soleus muscles of 15 normal cadaver specimens had four sequential releases: a single gastrocnemius recession, a second gastrocnemius recession, a single soleus recession, and an Achilles tenotomy. Ankle dorsiflexion was measured with a goniometer initially, after each muscle recession, and after the tenotomy., Results: After the second gastrocnemius recession, the average increase in ankle dorsiflexion measured 14 degrees with the knee extended and 8 degrees with the knee flexed., Conclusions: The Baumann procedure treats equinus contracture of the gastrocnemius muscle by improving ankle joint dorsiflexion. The procedure is indicated when the results of the Silfverskiöld test are positive.

Methods: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus (TAC) + mycophenolate mofetil (MMF), TAC + azathioprine (AZA), or cyclosporine (Neoral; CsA) + MMF. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function (DGF). Patients were followed-up for 3 years., Results: The results at 3 years corroborate and extend the findings of the 2-year results. Patients with DGF treated with TAC+MMF experienced an increase in 3-year allograft survival compared with patients receiving CsA+MMF (84.1% vs. 49.9%, P=0.02). Patients randomized to either treatment arm containing TAC exhibited numerically superior kidney function when compared with CsA. During the 3 years, new-onset insulin dependence occurred in 6, 3, and 11 patients in the TAC+MMF, CsA+MMF, and TAC+AZA treatment arms, respectively. Furthermore, patients randomized to TAC+MMF received significantly lower doses of MMF as compared with those who received CsA+MMF., Conclusion: All three immunosuppressive regimens provided excellent safety and efficacy. However, the best results overall were achieved with TAC+MMF. The combination may provide particular benefit to kidney allograft recipients with DGF. In patients who experienced DGF, graft survival was better at 3 years in those patients receiving TAC in combination with either MMF or AZA as compared with the patients receiving CsA with MMF.

Background: A previous report described the 1-year results of a prospective, randomized trial designed to investigate the optimal combination of immunosuppressants in kidney transplantation. Recipients of first cadaveric kidney allografts were treated with tacrolimus+mycophenolate mofetil (MMF), cyclosporine oral solution (modified) (CsA)+MMF, or tacrolimus+azathioprine (AZA). Results at 1 year revealed that optimal efficacy and safety were achieved with a regimen containing tacrolimus+MMF. The present report describes results at 2 years., Methods: Two hundred twenty-three recipients of first cadaveric kidney allografts were randomized to receive tacrolimus+MMF, CsA+MMF, or tacrolimus+AZA. All regimens contained corticosteroids, and antibody induction was used only in patients who experienced delayed graft function. Patients were followed up for 2 years., Results: The results at 2 years corroborate and extend the findings of the previous report. Patients randomized to either treatment arm containing tacrolimus experienced improved kidney function. New-onset insulin dependence remained in four, three, and four patients in the tacrolimus+MMF, CsA+MMF, and tacrolimus+AZA treatment arms, respectively. Furthermore, patients with delayed graft function/acute tubular necrosis who were treated with tacrolimus+MMF experienced a 23% increase in allograft survival compared with patients receiving CsA+MMF (P=0.06). Patients randomized to tacrolimus+MMF received significantly lower doses of MMF compared with those administered CsA+MMF., Conclusions: All three immunosuppressive regi-mens provided excellent safety and efficacy. How-ever, the best results overall were achieved with tacrolimus+MMF. The combination may provide particular benefit to kidney allograft recipients who develop delayed graft function/acute tubular necrosis. Renal function at 2 years was better in the tacrolimus treatment groups compared with the CsA group.

Background: Our clinical trial was designed to investigate the optimal combination of immunosuppressants for renal transplantation., Methods: A randomized three-arm, parallel group, open label, prospective study was performed at 15 North American centers to compare three immunosuppressive regimens: tacrolimus + azathioprine (AZA) versus cyclosporine (Neoral) + mycophenolate mofetil (MMF) versus tacrolimus + MMF. All patients were first cadaveric kidney transplants receiving the same maintenance corticosteroid regimen. Only patients with delayed graft function (32%) received antilymphocyte induction. A total of 223 patients were randomized, transplanted, and followed for 1 year., Results: There were no significant differences in baseline demography between the three treatment groups. At 1 year the results are as follows: acute rejection 17% (95% confidence interval 9%, 26%) in tacrolimus + AZA; 20% (confidence interval 11%, 29%) in cyclosporine + MMF; and 15% (confidence interval 7%, 24%) in tacrolimus + MMF. The incidence of steroid resistant rejection requiring antilymphocyte therapy was 12% in the tacrolimus + AZA group, 11% in the cyclosporine + MMF group, and 4% in the tacrolimus + MMF group. There were no significant differences in overall patient or graft survival. Tacrolimus-treated patients had a lower incidence of hyperlipidemia through 6 months posttransplant. The incidence of posttransplant diabetes mellitus requiring insulin was 14% in the tacrolimus + AZA group, 7% in the cyclosporine + MMF and 7% in the tacrolimus + MMF groups., Conclusions: All regimens yielded similar acute rejection rates and graft survival, but the tacrolimus + MMF regimen was associated with the lowest rate of steroid resistant rejection requiring antilymphocyte therapy.